It is suggested in the literature, that pharmacologic agents are currently under study for cerebral resuscitation and such agents include calcium antagonists. See generally, N. G. Bircher, "Ischemic Brain Protection," Ann. Emerg. Med., 14:8 August 1985, pp 784-788 and S. E. Gisiold and P. A. Steen, "Drug Therapy in Brain Ischaemia", Br. J. Anaesth., 57, (1985), pp 96-109.
After a general disclosure of the value of calcium entry blockers in circulatory disorders results of selected clinical studies with flunarizine by A. Kappert, in "The Clinical Value of Calcium Entry Blockers in Circulatory Disorders. Effect of Flunarizine in Cerebro-Vascular and Peripheral Vascular Diseases," Inter. Angio., 3, 1984, pp 43-50, are said to show a positive, well documented effect on the symptoms of cerebrovascular insufficiency and on intermittent claudication in peripheral arteriosclerosis. Specific indications suggested by A. Kappert as a result of his clinical studies are migraine and vertigo. The mechanism of such effect and any significance for other calcium antagonists from these studies is not known and not predictive for the utility of the present invention, i.e., the treatment of occlusive stroke. ln fact, flunarizine is not active in the assay described hereinafter as the combined middle cerebral and ipsilateral common carotid artery occlusion (MCAO) in the rat. This is essentially a well-recognized screen for compounds active against stroke now used to show the method of use for compounds having activity for the treatment of stroke of the present invention. Thus, although it is reported by J. K. Deshpande and T. Wielock in the article "Amelioration of Ischemic Brain Damage by Postischemic Treatment with Flunarizine, Neurological Research, 1985, Volume 7, March, pp 27-29, that flunarizine significantly reduced neuronal necrosis, the same authors readily admit that the etiologic processes involved in the damage that follows an ischemic insult still have not been clearly defined.
In fact, D. P. Reedy, et al, "Effects of Verapamil on Acute Focal Cerebral Ischemia," in Neurosurgery, Vol. 12, No. 3, 1983, pp 272-6, report that verapamil, that is also a Ca++ entry blocking agent, did not improve regional cerebral blood flow and did not protect ischemic brain in acute focal cerebral ischemia. J. R. Berger, et al, "Calcium Channel Blocker: Trial in Global Brain Ischemia," Neurology, p 183, 33[Suppl. 2] April 1983 also studied the efficacy of verapamil in preventing ischemic brain injury in rats concluding that the results of this study suggest that calcium channel blockers are ineffective in the treatment of severe brain ischemia.
The unpredictability of a calcium blocker generally and specifically, i.e., nimodipine, is apparent in discussions by A. I. Faden, et al, "Evaluation of the Calcium Channel Antagonist Nimodipine in Experimental Spinal Chord Ischemia," J. Neurosurg., Vol. 60, April, 1984, pp 796-9 and P. A. Steen, et al, "Nimodipine Improves Cerebral Blood Flow and Neurologic Recovery After Complete Cerebral Ischemia in the Dog, Journal of Cerebral Blood Flow and Metabolism, 3:38-43, 1983.
Finally, although nine drugs; D-600, diltiazem, flunarizine, nicardipine, nifedipine, nimodipine, nitrendipine, verapamil, and triapamil, were studied against induced hypoxia and hyperexcitability by A. Wauquier, et al, "Calcium Entry Blockers as Cerebral Protecting Agents: Comparative Activity in Tests of Hypoxia and Hyperexcitability," Japan J. Pharmacol., 38, pp 1-7 (1985), the studies are not specifically indicative of activity of a method of use for the treatment of stroke as now found in the present invention.
Selected compounds which inhibit calcium influx in cells of vascular tissue are generally known antiischemic agents. For example, see European Patent Application No. 0 132 375 showing utility for antiischemic agents as useful in the treatment or prevention of a variety of cardiac conditions. Thus, although A. Wauquier, et al, says his tests are for brain hypoxia, the tests show effects on decapitated male rats and as such do not teach the present method of treating stroke. Similarly, the antiischemic effects of A. Wauquier, et al, are shown by general studies of the kind supporting the usefulness disclosed in European Patent Application No. 0 132 375 discussed immediately above. Thus, no teaching in A. Wauquier, et al, shows treatment of stroke.
For the above reasons, the present invention relates to the now discovered novel method of use for the treatment of stroke with a compound known as diltiazem, verapamil, or nifedipine in an effective amount for treating stroke in unit dosage form.